Obesity is defined as an increase in the amount of adipose tissue, and is a high risk factor in the development of diabetes, hyperlipidemia, and cardiovascular and metabolic diseases such as coronary heart disease (Non-Patent Documents 1 and 2). However, molecular mechanisms that can explain the relationship between obesity and these diseases have not been elucidated. Adipose tissue itself functions as a tissue that carries out triglyceride (TG) storage and free fatty acid (FFA)/glycerol release depending on the changing energy requirements (Non-Patent Document 1). Adipose tissue is an important endocrine organ that secretes a large number of biologically active substances called “adipokines” such as FFA (Non-Patent Document 3), adipsin (Non-Patent Document 4), tumor necrosis factor α (Non-Patent Document 5), leptin (Non-Patent Document 6), plasminogen activator inhibitor 1 (Non-Patent Document 7), and resistin (Non-Patent Document 8), and controls energy homeostasis in various ways.
Adiponectin or Acrp30 (Non-Patent Document 9 to 12) is an adipose tissue-derived hormone that has several biological functions. The level of plasma adiponectin is decreased in obesity and in insulin-resistance and type II diabetes (Non-Patent Document 13). Experiments using mice have confirmed that administration of adiponectin decreases the blood glucose level and improves insulin resistance (Non-Patent Documents 14 to 16). On the other hand, there are reports that when adiponectin is knocked out in mice, insulin resistance and morbid conditions of diabetes are observed (Non-Patent Documents 17 and 18).
The insulin sensitivity-inducing activity of adiponectin is presumed to be induced by increase in fatty acid oxidation through PPARα activation (Non-Patent Documents 19 and 20), or acutely via AMP kinase (Non-Patent Documents 21 and 22). In endothelial cells (human aortic endothelial cells: HAEC) and macrophages, adiponectin may have antiatherogenic properties which are similar to anti-inflammatory effects (Non-Patent Documents 23 and 24). It was shown that when adiponectin is highly expressed in apoE knockout mice, the expression of molecules related to inflammation decreases, and along with this, atherosclerosis is improved (Non-Patent Documents 19 and 25). Neointimal formation was increased in adiponectin knockout mice (Non-Patent Documents 17 and 26).
Recently, the cloning of cDNAs encoding adiponectin receptor (AdipoR) 1 and 2 was reported (Non-Patent Document 27 and Patent Document 1). AdipoR1 is expressed abundantly in skeletal muscle, whereas AdipoR2 is expressed mainly in the liver. AdipoR1 and R2 comprise seven transmembrane domains (Non-Patent Document 27), but they are presumed to be distinguishable from G protein-coupled receptors, both structurally and functionally (Non-Patent Documents 28 to 30). AdipoR1 and R2 function as receptors for globular and full-length adiponectin, and induce AMPK activation (Non-Patent Documents 21 and 22), PPARα ligand activation (Non-Patent Documents 19 and 20), and increased fatty acid oxidation and glucose uptake due to adiponectin (Non-Patent Document 27).    [Patent Document 1] WO2004/061108    [Non-Patent Document 1] Spiegelman, B. M. & Flier, J. S., Cell 87, 377-389 (1996).    [Non-Patent Document 2] Friedman, J. M., Nature 404, 632-634 (2000).    [Non-Patent Document 3] White, R. T. et al., J. Biol. Chem. 267, 9210-9213 (1992).    [Non-Patent Document 4] Hotamisligil, G. S. et. al., Science 259, 87-91, (1993).    [Non-Patent Document 5] Zhang, Y. et al., Nature 372, 425-432, (1994).    [Non-Patent Document 6] Shulman, G. I., J. Clin. Invest. 106, 171-176 (2000).    [Non-Patent Document 7] Shimomura, I. et al., Nat. Med. 2, 800-803 (1996).    [Non-Patent Document 8] Steppan, C. M. et al., Nature 409, 307-312 (2001).    [Non-Patent Document 9] Scherer, P. E. et al., J. Biol. Chem. 270, 26746-26749 (1995).    [Non-Patent Document 10] Hu, E., Liang, P. & Spiegelman, B. M., J. Biol. Chem. 271, 10697-10703 (1996).    [Non-Patent Document 11] Maeda, K. et al. Biochem. Biophys. Res. Commun. 221, 286-296 (1996).    [Non-Patent Document 12] Nakano, Y, et al., J. Biochem. (Tokyo) 120, 802-812 (1996).    [Non-Patent Document 13] Hotta, K. et al., Arterioscler. Thromb. Vasc. Biol. 20, 1595-1599, 2000.    [Non-Patent Document 14] Fruebis, J. et al., Proc. Natl. Acad. Sci. USA. 98, 2005-2010 (2001).    [Non-Patent Document 15] Yamauchi, T. et al., Nat. Med. 7, 941-946 (2001).    [Non-Patent Document 16] Berg, A. H. et al., Nat. Med. 7, 947-953 (2001).    [Non-Patent Document 17] Kubota, N. et al., J. Biol. Chem. 277, 25863-25866 (2002).    [Non-Patent Document 18] Maeda, N. et al., Nat. Med. 8, 731-737 (2002).    [Non-Patent Document 19] Kersten, S. et al., Nature 405, 421-424 (2000).    [Non-Patent Document 20] Yamauchi, T. et al., J. Biol. Chem. 278, 2461-2468 (2003).    [Non-Patent Document 21] Yamauchi, T. et al., Nat. Med. 8, 1288-1295 (2002).    [Non-Patent Document 22] Tomas, E. et al., Proc. Natl. Acad. Sci. USA. 99, 16309-16313 (2002).    [Non-Patent Document 23] Ouchi, N. et al., Circulation 103, 1057-1063 (2001).    [Non-Patent Document 24] Yokota, T. et al., Blood 96, 1723-1732 (2000).    [Non-Patent Document 25] Okamoto, Y et al., Circulation 106, 2767-2770 (2002).    [Non-Patent Document 26] Matsuda, M. et al., J. Biol. Chem. 277, 37487-37491 (2002).    [Non-Patent Document 27] Yamauchi, T. et al., Nature 423, 762-769 (2003).    [Non-Patent Document 28] Wess, J., FASEB. J. 11, 346-354 (1997).    [Non-Patent Document 29] Yokomizo, T. et al., Nature 387, 620-624 (1997).    [Non-Patent Document 30] Scheer, A. et al., EMBO. J. 15, 3566-3578 (1996).